PROJECT SUIWMARY (See instructions): Genetic and genomic approaches have been highly productive in identifying new biology that underlies human health and disease. Advances in the last 5 years have been dramatically accelerated by the development, with support of the O'Brien Center, of exome sequencing, a method for rapiidly and inexpensively sequencing all the protein-coding genes in the genome. Success in disease gene discovery requires diverse skill sets and effective collaborations among clinicians, basic scientists, and biostatisticians. Necessary tools include expertise in clinical medicine, knowledge of the regulatory environment to permit development of appropriate HIC protocols, expertise in study design to ensure that studies are adequately powered, technological expertise to ensure that lab-based approaches remain at the cutting edge of the field, and first-rate biostatistical analysis of results to ensure that findings are valid and robust. Yale has developed expertise in each of these areas and as a consequence Yale investigators have been at the forefront of this endeavor with leaders in gene finding for Mendelian disease and complex traits across diverse disciplines. In the last 5 years, projects fostered by the Yale O'Brien center have led to discovery of new disease genes for a wide array of kidney diseases, with many more discovery projects underway with leading investigators from the NIDDK community. This core will continue to provide key infrastructure support for all steps along the path to discovery, including development of HIC protocols, patient recruitment, tools production and analysis of next generation DNA sequencing and other large data sets. This core will provide effective training for students, fellows and faculty and will help engage new investigators in translational research.